The applicant requests support from the NIMH Research Scientist Development Award Level I to pursue molecular genetic studies of major affective illness. Very large families with a high density of affective illness have been identified and will continue to be characterized using standardized and reliable interviews and diagnostic criteria. Lymphoblastoid cell lines will continue to be established on family members. The applicant will receive further training in recombinant DNA technology and will utilize restriction fragment length polymorphisms (RFLPs) in sib-pair and maximum likelihood (LOD score) genetic linkage analyses of the affective disorder families. Highly informative insertion/deletion RFLPs in the previously "silent" or unexamined regions of the genome as well as genes or chromosomal regions that have been implicated in affective illness will be examined for linkage to affective illness or affective illness traits by maximum likelihood (LOD score) analyses and sib- pair methodologies. Furthermore, tests of genetic heterogeneity across affective disorder families will be performed. Genomic regions to be examined include chromosome llp markers, found to be linked to affective disorder in Old Order Amish families. Additionally, neuropeptides that have been implicated in the pathogenesis of affective disorders, corticotropin releasing factor (CRF) and somatostatin (SRIF), will be analyzed for linkage. Course-work in population genetics, neurobiology and molecular biology will complement the candidate's developmental training. The linkage of a susceptibility for affective illness gene will achieve a major step towards the isolation and characterization of an etiological gene, thereby leading to improved heterozygote and at risk diagnosis and to the development of more effective. therapeutic approaches to affective illness.